[R01] Cytosolic SINE retrotransposable element cDNA and mitochondrial DNA in aging retina
Ente: National Institute on Aging
Scadenza: 2028-04-30
Importo max: 631.751 EUR
Paese: US
Descrizione
PROJECT SUMMARY
The retinal pigmented epithelium (RPE) is an amitotic, long-lived cell type that supports healthy visual function
for numerous decades. The aging retina displays pathologic features that are exaggerated in a complex disease
called age-related macular degeneration (AMD). Progressive degeneration of the aging RPE is a hallmark of
geographic atrophy, a late-stage of AMD that causes vision loss. We recently discovered an excess abundance
of cytosolic complementary DNA derived from the SINE retrotransposon element (RTE) Alu family in the RPE of
human eyes with geographic atrophy and that cytosolic Alu cDNAs are highly cytotoxic to the RPE in animal and
human cell-based studies. These Alu cDNAs are produced via reverse transcription of Alu RNAs by the long-
interspersed nuclear element-1 (L1). We also found that Alu cDNAs trigger the cytosolic escape of mitochondrial
DNA (mtDNA), and together these two cytosolic DNAs collaborate, in mechanistically unclear ways, to activate
a multifaceted innate immune response that results in cell death. To gain a better understanding of the
combinatory impact of Alu cDNAs and mtDNA and their causal contribution to aging in the retina, we will (1)
create temporal, spatial, and sequence topographic maps of Alu cDNA subfamilies and mtDNA in young, healthy
aged, and AMD-affected human eyes; (2) probe the stimuli for and mechanisms of Alu cDNA generation in aging
by investigating whether L1 regulators influence Alu cDNA production and retinal toxicity; and (3) elucidate the
pathway of mitochondrial dysfunction triggered by Alu cDNA and the noncanonical inflammatory pathways
triggered by Alu cDNA and mtDNA joint activity that are responsible for retinal cell death. This proposal is
responsive to RFA-AG-23-015 as it will provide mechanistic insights into how cytosolic Alu cDNAs and mtDNA
mediate interactions of aging hallmarks and modulate healthspan by mapping their sequence and expression
during aging, determining the regulation of their biogenesis, and delineating how they conspire with each other
to promote cellular dysfunction in aging. Completion of these studies will reveal previously unexplored pathways
with therapeutic relevance for developing transformative therapies to improve visual healthspan and potentially
cognitive healthspan, as conditions such as Alzheimer’s disease share epidemiological and mechanistic features
with AMD.
Istituzione: UNIVERSITY OF VIRGINIA
PI: Jayakrishna Ambati, Bradley David Gelfand
Progetto: 5R01AG082748-04
Settori: National Institute on Aging
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